一个开放的标签,单中心,进行I期研究以确定绝对生物利用度和吸收,分布,新陈代谢,和capivasertib的排泄-一种有效的,健康男性的选择性AKT丝氨酸/苏氨酸激酶抑制剂。在第1部分中,六名参与者接受了单次口服剂量的capivasertib(400mg;片剂),然后接受了[14C]放射性标记的静脉微剂量的capivasertib(100µg)。经过14天的清洗,5名参与者进入第2部分,并接受了单次口服剂量的[14C]capivasertib(400mg;溶液).在第1部分中,capivasertib的最大观察浓度的中位时间为1.7小时,几何平均终末消除半衰期为12.9小时,绝对生物利用度估计为28.6%(90%置信区间,23.9至34.2)。在第2部分中,在168小时的采样期内回收了高比例的所施用放射性(平均回收率:95.1%[粪便,50.4%;尿液,44.7%])。尿液中不变的capivasertib占总剂量的7.4%,占全身可用药物的21.1%。几何平均肾清除率为8.3L/h,提示活跃的肾小管分泌。在血浆中鉴定出12种代谢物。M11(AZ14102143)-capivasertib的葡糖苷酸缀合物,作为AKT丝氨酸/苏氨酸激酶抑制剂是最丰富的,平均占血浆药物相关曲线下面积的78.4%。在排泄物中鉴定出的22种代谢物中,M11是最丰富的(平均28.2%的给药剂量),表明直接葡萄糖醛酸化是代谢的主要途径之一。没有发现新的安全问题。意义声明本研究提供了capivasertib的药代动力学特征-一种有效的,选择性AKT丝氨酸/苏氨酸激酶(AKT)抑制剂-包括绝对生物利用度,质量平衡,和人类的代谢命运;这些发现正被用来为进一步的临床发展提供信息。绝对生物利用度估计为28.6%,在168小时内,排泄物中给药剂量的平均回收率为95.1%。M11(AZ14102143)-葡糖苷酸缀合物,作为AKT抑制剂无活性-是血浆和排泄物中最丰富的已鉴定代谢物。
An open-label, single-center, phase I
study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective
AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 μg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an
AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This
study provides characterization of the pharmacokinetics of capivasertib-a potent, selective
AKT serine/threonine kinase (
AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.